The cerebral cortex is the largest and most complex component of the mammalian brain, reaching its pinnacle in humans. The neocortex is the largest region of the cerebral cortex and is organized into "areas" that are functionally unique subdivisions distinguished by differences in cytoarchitecture, connectivity, and patterned gene expression. The specification of neocortical areas is controlled by an interplay between genetic regulation intrinsic to the neocortex, characterized by transcription factors (TFs) expressed by cortical progenitors, and extrinsic influences such as thalamocortical (TCA) input that relays sensory information to cortical areas. Proper area patterning of the cortex is a critical developmental event, because cortical areas form the basis for sensory perception, the control of our movements, and mediate our thoughts and behaviors. Although of undeniable importance, relatively little is known about the genetics of arealization. Current findings indicate a regulatory hierarchy that begins with patterning centers at the perimeter of the cerebral cortex that secrete morphogens, which in turn establish the graded expression of TFs in cortical progenitors that specify their area identities as well as those of their neuronal progeny. The major goal of this grant is to determine the TFs that control arealization, and define their roles in specifying area identities. The major issues to be addressed include: (1) defining the TFs that control the patterning of frontal / motor areas, and caudal / sensory (C/S) areas, as well as the interactions between these TFs to balance the rostral-caudal area patterning of the cortex, and (2) to distinguish roles for these TFs in the intrinsic genetic specification of area-specific properties in the cortical plate versus roles for TCA input in controlling the differentiation of area-specific properties and specializations that distinguish areas. Surprisingly, the size of each primary area in human neocortex varies by as much as two- to three-fold within the normal population. In mice, the sizes of a primary area can also vary significantly between individuals. These variations in area size can have dramatic effects on behavior. For example, genetic manipulations during embryonic development that result in proportional decreases or increases in the sizes primary areas in adults result in significant deficiencies at modality-specific behaviors. These findings indicate that areas have an optimal size, and underscore the importance of establishing during development the appropriate expression levels of TFs that specify area identities, as changes in them can result in a proportional change in area size, and thereby these early developmental events can have a prominent influence on behavior later in life, affecting performance and likely underlying many forms of cognitive dysfunction and neurological disorders. Therefore, the third major goal of this proposal is to establish the mouse as a model for relating differences in area patterning to variations in TF expression, and after validating this relationship, to use it as a basis to define roles for these TFs in area patterning in humans. PUBLIC HEALTH RELEVANCE: The neocortex is the largest and most complex component of the mammalian brain, reaching a pinnacle in humans. This proposal addresses the genetic mechanisms that control the patterning of the neocortex intro areas-- anatomically and functionally distinct subdivisions responsible for sensory perception, voluntary movements, thinking and behaviors. The findings from the proposed aims will form a basis of understanding of cognitive dysfunction and neurological disorders.